8-6506429-C-G

Variant names:

• chr8-6506429-C-G
• rs2442468
• NM_024596.5:c.2214+6500C>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_024596.5(MCPH1):​c.2214+6500C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.527 in 151,926 control chromosomes in the GnomAD database, including 21,916 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.53 (21916 hom., cov: 31)
• Consequence: MCPH1 NM_024596.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.293
• Publications: 6 publications found

Genes affected

MCPH1 (HGNC:6954): (microcephalin 1) This gene encodes a DNA damage response protein. The encoded protein may play a role in G2/M checkpoint arrest via maintenance of inhibitory phosphorylation of cyclin-dependent kinase 1. Mutations in this gene have been associated with primary autosomal recessive microcephaly 1 and premature chromosome condensation syndrome. Alternatively spliced transcript variants have been described. [provided by RefSeq, Feb 2010]

ANGPT2 (HGNC:485): (angiopoietin 2) This gene belongs to the angiopoietin family of growth factors. The protein encoded by this gene is an antagonist of angiopoietin 1, and both angiopoietin 1 and angiopoietin 2 are ligands for the endothelial TEK receptor tyrosine kinase. Angiopoietin 2 is upregulated in multiple inflammatory diseases and is implicated in the direct control of inflammation-related signaling pathways. The encoded protein affects angiogenesis during embryogenesis and tumorigenesis, disrupts the vascular remodeling ability of angiopoietin 1, and may induce endothelial cell apoptosis. This gene serves a prognostic biomarker for acute respiratory distress syndrome. [provided by RefSeq, Aug 2020]

ANGPT2 Gene-Disease associations (from GenCC):

• lymphatic malformation 10

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.65 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024596.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MCPH1	NM_024596.5	MANE Select	c.2214+6500C>G		intron	N/A	NP_078872.3	Q8NEM0-1
	ANGPT2	NM_001118887.2	MANE Select	c.1327+2503G>C		intron	N/A	NP_001112359.1	O15123-3
	MCPH1	NM_001322042.2		c.2214+6500C>G		intron	N/A	NP_001308971.2	A0A8I5KV10

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MCPH1	ENST00000344683.10	TSL:1 MANE Select	c.2214+6500C>G		intron	N/A	ENSP00000342924.5	Q8NEM0-1
	ANGPT2	ENST00000629816.3	TSL:1 MANE Select	c.1327+2503G>C		intron	N/A	ENSP00000486858.2	O15123-3
	ANGPT2	ENST00000325203.9	TSL:1	c.1330+2503G>C		intron	N/A	ENSP00000314897.5	O15123-1

Frequencies

GnomAD3 genomes AF: 0.527 AC: 80052 AN: 151806 Hom.: 21889 Cov.: 31

Gnomad AFR AF: 0.656

Gnomad AMI AF: 0.399

Gnomad AMR AF: 0.393

Gnomad ASJ AF: 0.500

Gnomad EAS AF: 0.271

Gnomad SAS AF: 0.478

Gnomad FIN AF: 0.472

Gnomad MID AF: 0.589

Gnomad NFE AF: 0.513

Gnomad OTH AF: 0.530

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.527 AC: 80120 AN: 151926 Hom.: 21916 Cov.: 31 AF XY: 0.521 AC XY: 38666 AN XY: 74252

African (AFR) AF: 0.657 AC: 27187 AN: 41398

American (AMR) AF: 0.393 AC: 5993 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.500 AC: 1734 AN: 3468

East Asian (EAS) AF: 0.272 AC: 1404 AN: 5168

South Asian (SAS) AF: 0.477 AC: 2294 AN: 4808

European-Finnish (FIN) AF: 0.472 AC: 4977 AN: 10546

Middle Eastern (MID) AF: 0.588 AC: 173 AN: 294

European-Non Finnish (NFE) AF: 0.513 AC: 34887 AN: 67962

Other (OTH) AF: 0.525 AC: 1108 AN: 2112

Alfa AF: 0.351 Hom.: 815

Bravo AF: 0.526

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	4.2
DANN	Benign	0.70
PhyloP100		-0.29
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs2442468; hg19: chr8-6363950;